ClinVar Genomic variation as it relates to human health

In affected members of 2 unrelated families with autosomal dominant inheritance of Gerstmann-Straussler disease (GSD; 137440), Hsiao et al. (1989) identified a C-to-T transition in the PRNP gene, resulting in a pro102-to-leu (P102L) substitution. The mutation was not identified in 100 Caucasian control individuals. The authors reported that the families presented with ataxia. One of the families also had a polymorphism resulting from a 'silent' A-to-G substitution at the third position of alanine codon 117. Goldgaber et al. (1989) identified the P102L mutation in 3 affected members of a family with GSD. The base substitution responsible for the change in codon 102 may have involved deamination of a methylated cytosine situated 5-prime to guanine, a CpG mutation. The proline at codon 102 seems to be highly conserved, as all rodent proline genes sequenced to date also encode a proline at the equivalent codon. Doh-ura et al. (1989) reported that the P102L mutation was identified in all 11 Japanese GSD patients studied. Speer et al. (1991) found linkage to the P102L mutation in a large German family with GSD. Three asymptomatic members of the German family carried the substitution; their ages, 41, 42, and 42, were below the mean for age of onset (47 years) for GSD in this family. In a 36-year-old woman with GSD who belonged to the original family reported by Gerstmann et al. (1936) and Seitelberger (1962), Kretzschmar et al. (1991) identified a heterozygous P102L mutation in the PRNP gene. Goldfarb et al. (1990) excluded the P102L mutation in patients with CJD and kuru, suggesting that it is specific for GSD. Goldhammer et al. (1993) described an Ashkenazi Jewish family living in Israel in which Gerstmann-Straussler syndrome was due to the P102L mutation in the PRNP gene. Doh-ura et al. (1990) demonstrated the P102L mutation in 6 of 7 patients with Creutzfeldt-Jakob disease with congophilic kuru plaques. No patient with CJD without congophilic kuru plaques had this allele. They also found the leu102 allele in some unaffected relatives of 3 patients, although there was no known familial occurrence of a similar neurologic disorder. Doh-ura et al. (1990) concluded that CJD with congophilic kuru plaques should be categorized as Gerstmann-Straussler syndrome, not CJD. Parchi et al. (1998) reported 7 unrelated patients with GSS who carried a heterozygous P102L mutation. Two major types of PrP(res) were identified: an unglycosylated 8-kD fragment, found in all patients, and an additional unglycosylated 21-kD fragment, found in 5 of the 7 patients. Additional 27- and 29-kD fragments that were glycosylated forms of the 21-kD fragment were also found in the 5 patients with the 21-kD fragment. The 8-kD fragment was ragged at both the N- and C-terminal ends, whereas the 21-kD fragment was truncated only at the N-terminal end. The 8-kD fragment correlated with the presence of amyloid plaques, whereas the 21-kD fragment correlated with spongiform degeneration. These PrP(res) fragments were present in vivo. The findings suggested that the neuropathology of prion diseases largely depends on the type of PrP(res) fragment. In neuroblastoma cells transfected with the P102L mutation, Mishra et al. (2002) showed that the processing and turnover of the prion protein was altered, resulting in decreased expression of a normal 18-kD fragment and increased accumulation of a 20-kD fragment on the surface of these cells. The authors suggested that this alteration may render the cells more susceptible to pathogenic prion protein infection and toxicity via amyloidogenesis or amplification of a neurotoxic signal initiated by a pathogenic prion protein. (less)